Chromosome Biology

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

All animals develop from a single fertilized egg cell, from which all cell types in the adult must be derived. This process occurs through a series of precursor cells with increasingly restricted lineage potential. Since the cells of the body have different functions, they must express different sets of genes. Cells do not lose genetic information during development, and so gene expression and silencing must be tightly controlled. Inappropriate gene expression occurs in many cancers, for example.||The work of the Chromosome Biology Group aims to understand the basic mechanisms underlying the control of gene expression. We are interested in whether the way in which genes are packaged (i.e. how accessible they are to regulatory factors) and distributed within the cell nucleus plays a role in the control of their activity. We investigate this during blood cell development because the cells are easy to obtain and grow in culture, and can be induced to mature by the addition of factors to the tissue culture medium. We then use a variety of techniques to characterise the changes in the organization and expression of genes. The research is important because we hope that it will allow us to understand the control of gene expression at a fundamental level and, therefore, to understand how cell identity is defined and maintained. We hope that our work will contribute to an understanding of how diseases involving incorrect gene expression arise. Correction of such defects through gene therapy is the ultimate future goal.

Technical Summary

All cells contain the same genetic information (genes) yet different cell types are characterized by different patterns of gene expression and silencing. The epigenetic control of gene expression is, therefore, a recent area of interest. Chromatin, rather than the linear DNA sequence, is thought to convey the genetic identity of a cell. Proteins involved in the formation of heterochromatin, the more compact and inaccessible form of chromatin, may also be involved in gene silencing during cellular differentiation and lineage commitment. The Chromosome Biology Group investigates the relationship between chromatin structure, nuclear organization and DNA condensation during regulated gene expression, in order to understand the epigenetic control of genome function at the molecular level. Dividing lymphocytes and developing erythroblasts provide model systems.||We are currently investigating the role of heterochromatin protein 1 (HP1) in the formation of facultative heterochromatin during erythroid maturation. The ability of erythroid cells lacking HP1 proteins to mature is under investigation. Homology between mouse and human HP1 proteins makes it likely that facultative heterochromatin formation and the control of gene expression will be similar in mice and humans. Antibodies against specifically modified histones (known to be associated with different chromatin states) have been used to compare erythroblasts containing or lacking HP1 proteins. PCR, FACS and microscopy-based techniques are being employed in order to assess the maturation potential of erythroid cells retaining or lacking the HP1 proteins, and to compare their gene expression profiles during erythroid maturation.|||The degree of reversibility of gene silencing and activity impacts on our understanding of gene reprogramming during cloning. Genes are packaged into chromatin consisting of nucleosomes, which can be modified by methylation or acetylation. These modifications have been characterized extensively and correlated with the transcriptional status of genes, but less is known about the functional significance of higher orders of chromatin organization within the mammalian nucleus. Another current area of research investigates the comparative strength of globin gene silencing in lymphocyte nuclei reprogrammed through heterokaryon formation between lymphocytes (in which the globin genes are silent but differently compartmentalized) and erythroid cells (in which the globin genes are expressed).| |It is hoped that an improved understanding of the epigenetic regulation of gene expression and silencing during erythropoiesis will contribute to our understanding of blood cell pathologies. These projects may contribute towards the wider goal of understanding the mechanisms involved in the specification of cell identity during mammalian development.

Publications


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Piccolo FM (2011) Using heterokaryons to understand pluripotency and reprogramming. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
 
Description The functional significance of sub-nuclear protein distribution 
Organisation University of Buenos Aires
Department The Institute of Biology and Experimental Medicine (IBYME)
Country Argentina, Argentine Republic 
Sector Academic/University 
PI Contribution Sponsored the research, advised on the project and contributed protocols for the experiements.
Impact International collaboration and publication, PMID: 21122806. Argentinian researcher visited the CSC to give a talk about the results.
Start Year 2008
 
Description The genetic defects resulting in Seckel syndrome and related syndromes 
Organisation Karadeniz Technical University
Department Department of Medical Biology
Country Turkey, Republic of 
Sector Academic/University 
PI Contribution Fluroescence in situ hybridization experiments to characterise the nature of the defect caused by the genetic defect identified in the Institute fur Humangenetic's group. Contribution to the resulting manuscript with discussions and corrections.
Impact International collaboration and publication, PMID: 21131973. An additional paper has been submitted on a related defect (on which the PI is first author). Experimental contributions are ongoing.
Start Year 2009
 
Description The genetic defects resulting in Seckel syndrome and related syndromes 
Organisation University Hospital
Department Institute of Human Genetics
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution Fluroescence in situ hybridization experiments to characterise the nature of the defect caused by the genetic defect identified in the Institute fur Humangenetic's group. Contribution to the resulting manuscript with discussions and corrections.
Impact International collaboration and publication, PMID: 21131973. An additional paper has been submitted on a related defect (on which the PI is first author). Experimental contributions are ongoing.
Start Year 2009
 
Description The role of the HP1 proteins in differentiation 
Organisation Leibniz Association
Department Leibniz Center for Medicine and Biosciences
Country Germany, Federal Republic of 
Sector Public 
PI Contribution Received murine fetal livers from mice deficient in HP1 proteins (constructed in the Borstel laboratory) for analysis of definitive erythroid differentiation in the absence of these silencing proteins.
Collaborator Contribution The project allowed the PI to advertise for and employ post-doctoral researchers for the group.
Impact Paper submitted but as yet unpublished: 'Heterochromatin Protein 1 gamma (HP1gamma) can substitute for HP1alpha and HP1beta in the assembly and maintenance of constitutive and facultative heterochromatin during definitive erythropoiesis' Aucott RL, Brown JP, Singh PB and Brown KE.
Start Year 2006